Rocky Road for Mitochondrial Transfer

Action Points

Altering mitochondria during in vitro fertilization (IVF) as a means of preventing disease transmission won't be moving to human trials any time soon.

Note that the technology has been portrayed as controversial because it involves DNA from three different people -- mitochondrial DNA from a healthy donor, along with the nucleus containing the mother's genetic information, and the father's genes, although that is quite different from being able to select for individual traits.

Altering mitochondria during in vitro fertilization (IVF) as a means of preventing disease transmission won't be moving to human trials any time soon, according to experts at a 2-day FDA hearing.

There aren't enough preclinical data to ensure safety and efficacy of mitochondrial transfer, and questions remain about potential risks to the mother and fetus, Evan Snyder, MD, PhD, of Sanford-Burnham Medical Research Inst in La Jolla, Calif., and chair of the meeting, told MedPage Today.

"We need more preclinical data to know whether this is even effective," he said in an interview. "Right now, theoretically, there are potential risks to the mother and fetus. A lot more data need to be accumulated."

He said that while "important steps have been made" since the advent of the technology in the 1990s, researchers still aren't confident that it should move into human trials. For instance, there's been no direct comparison of the various strategies for transfering mitochondria -- including ooplasm transfer, pronuclear transfer, and spindle transfer -- to determine which is most effective.

Rocky Road

Mitochondrial transfer -- which some have termed "three-person embryo transfer" -- was developed to prevent transmission of mitochondrial disease from mother to baby. This type of disease is rare in the U.S., with about 1,000 to 4,000 cases per year.

Although there are different approaches, the basic idea of the procedure is to use the nucleus of the mother's egg cell to retain her genetic identity while replacing the diseased mitochondria, which surround the nucleus.

Researchers have been working with the technology for decades but have often found their efforts stymied.

James Grifo, MD, PhD, director of the NYU Fertility Center, had just receive a half-million-dollar private donation to move years worth of animal research on nuclear transfer into human trials when his Institutional Review Board shut those efforts down in 1998.

A colleague, John Zhang, MD, moved their efforts to China, where one woman became pregnant after a 5-embryo transfer (the chance of implantation was 1 in 5 based on animal studies).

She conceived triplets, which were reduced to twins, but she lost all of the fetuses -- and the work was eventually halted by Chinese authorities, Grifo said.

In 2001, the FDA also stopped the work of a New Jersey fertility clinic that was performing the ooplasm transfer technique in humans.

Led by Jacques Cohen, MD, researchers treated 17 infertile women with the procedure, but regulators at the FDA hearing noted that one child was born with a missing chromosome, and another had autism.

Grifo said it's not clear whether these women and their children are still being followed up. A spokesperson said Cohen could not comment for this story because he was out of the country.

Recent Efforts

More recent efforts into mitochondrial transfer in the U.S. have been led by Shoukhrat Mitalipov, PhD, of Oregon Health & Science University.

Experts say his work is the most advanced because he has been able to produce several healthy macaque monkeys following mitochondrial transfer.

But his group hasn't addressed whether the experiments work when the female starts out with abnormal mitochondria, Snyder said. Mitalipov has never worked with eggs that have mitochondrial disease.

"The feasibility that technique could work because the technical expertise is there," Snyder said, "but it's never been tried to show that one could repelace an abnormal mitochondria with normal mitochondria and get normal mitochondria" in the offspring.

Mitalipov did not return requests for comment.

British Researchers First?

Grifo said it's likely that British researchers will be first to move the technique into human trials.

A team at Newcastle University in England, which includes Mary Herbert, MD, who spoke at the FDA hearing, has also been pushing ahead on mitochondrial transfer.

A ban on using government funds for germline manipulation prevents a significant amount of funding for the research, but U.K. regulators are in the process of making an exception for mitochondrial transfer.

Herbert noted, however, that outcomes are still far away as researchers continue to work on a to-do list requested by the licensing authority, which will require more animal studies and human stem cell work.

Designer Babies?

Grifo noted that the technology has been portrayed as controversial because it involves DNA from three different people -- mitochondrial DNA from a healthy donor, along with the nucleus containing the mother's genetic information, and the father's genes.

But that's a far cry from being able to select for individual traits, he noted.

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